Дата публикации: 18 октября 2021
Автор(ы): Leonid ALEXEYEV
Публикатор: Научная библиотека Порталус
Источник: (c) Science in Russia, №6, 2012, C.4-11
Номер публикации: №1634550951

Leonid ALEXEYEV, (c)

by Leonid ALEXEYEV, corresponding member of the Russian Academy of Medicine, Immunology Institute, deputy director; Federal Medicobiological Agency, Moscow, Russia


Human genome sequencing is a breakthrough achievement of the late 20th and early 21st centuries. Next in order come proteic products of particular genes. Hence the now current term, "postgenomic technologies", or research in genome functions realized through proteins coded for by particular genes.


The genome has a structure the proteomics* of which has been primary with respect to genomics. This structure is known as the Major Histocompatibility Complex, or MHC; in humans this is the HLA, or Human Leukocyte Antigens system. Its first proteic product was discovered in 1956 by the French immunologist Jean Dausset (Nobel Prize, 1980). In the 1970s it was intended to change its name into a "System of Immune Response Genes"; yet it was decided to keep the term as it was, for it connotes immune response genes and their products, the HLA antigens, anyway.


The international community of immunogeneticists set up in the 1960s unites today dozens of thousands of research scientists across the world* cooperating within the framework of international four-year programs implemented under the guidance of the organizing committees of meetings and conferences on immune response genetics.


In the 1960s, 1970s and 1980s the focus was on proteic products of H LA genes, the H LA antigens. In those days molecular geneticists were unable to make a thorough


* Proteomics. a molecular biology discipline involved with a study of cell proteomes, or a set of proteins in a cell in a particular phase of its growth.--Ed.


* Working in Europe is the European Federation of Immunogeneticists (EFI); in the United States, this is the American Society of Histocompatibility and Immunogenetics (ASHI); in Asia and Oceania, the ASE-ATTA organizations.--Aurh.

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HLA molecules and immune response. A stage in the recognition of a peptide by class II molecules, and the effector stage mediated by class I HLA molecule. A response to the peptide takes place only if it is presented by an HLA molecule of the host organism.



study of the HLA genome for lack of adequate molecular genetics methods.


The first problem on the agenda was selecting histo-compatible donor-recipient pairs for the purpose of organ and tissue transplantation. Yet it became clear soon that the biological role of HLA antigens is much broader than that, for they are responsible for certain physiological functions not directly related to the immune response. In particular, they orchestrate the physiological interaction of all nucleus-containing cells of the human organism, that is ensure its very existence. This interaction is predicated on the identity of HLA antigens expressed on the interacting cells of the same organism.


HLA antigens also account for the recognition and destruction of agents carrying an imprint of foreign genetic information in the form of alien proteic products. This is likewise true of cells that contain foreign H LA antigens, including degenerated and cancer cells of the host organism. It was in the "pregenomic period" of HLA studies, in 1960 to 1985, that fundamental, basic studies were made on the biological role of HLA antigens. The Swiss immunologist Rolf Zinkernagel and his Austrian colleague Peter Doherty (both merited a Nobel Prize in 1996) detected a phenomenon of the "double recognition" of foreign immunogenic peptides.


One such peptide, the immune response initiator, is recognized by the T-cells* receptor (TCR) triggering an immune response to a foreign peptide only if this peptide is presented to the receptor by a host HLA molecule, barring cases when the peptide is presented by HLA foreign molecules fully identical with molecules of the host organism. Now if a foreign immunogenic peptide is presented by the TCR of a foreign HLA molecule, the immune response would not be directed against this peptide, but against the foreign HLA molecule as the most potent from among immunogenes known to date.


Using crystallography methods, Pamela Bjorkman of the United States detected fine interactive mechanisms involving the immunodominant peptide and the HLA molecule presenting it. Ultimately it became possible to elucidate principles whereby immune response genetic control is realized. These principles boil down to this: a response to an immunodominant peptide within the antigen-bonding region (groove) of a molecule depends on the presence of binding sites specific for this particular peptide. The immune response fails if they are absent. This pattern applies both to the response to a pathogenic infectious agent and to a vaccine administered for


* T-cells, the central link of the T-cell immune response; they control its potency and duration.--Ed.

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Immunodominant peptides presented by HLA molecules (crystallogram). Group A, a situation when the antigen-presenting groove has peptide-binding sites (asterisks); such sites are absent in group B.


the prevention of a particular disease. This phenomenon underlies the immune response control and explains the specificity of this response. One learned the cause of the genetically conditioned "non-response" to infectious and other foreign agents. But it was not clear yet whether it was possible at all to deal with a "defect" like that. If it was, then how?


This problem was finally resolved by two Russian biologists, Rem Petrov and Rachim Khaitov, who found an essentially fresh approach in coming to deal with the immunogenetic "non-response". Their method, "Immune Response Phenotypic Correction", ushered in a promising line in vaccinology.* The authors succeeded in upgrading individuals showing a weak phenotypic response to a given gene (infection) into ones with an active response. This was achieved by acting on the antigen molecule by immunomodulating agents. As a result new sites of genes involved in the immune response to this particular antigen get implicated in the immune response. This approach opens up great opportunities in using nanotechnologies in the field of a targeted genetic "reconstruction" of the immune response.*


Reproduction of offspring is the Number One function of immune response genes. This is true of all biological species.


One essential condition for normal pregnancy and healthy progeny with a sound immune system: both parents should be incompatible in immune response genes. This situation ensures an immunogenetic diversity of Homo sapiens and other species of the animal kingdom since HLA genes are inherited by the codominant type when a baby takes in by half (HLA haplotype) from the complete HLA set (genotype) from every parent. If the father and mother have common HLA antigens (say, in cognate marriages), their child may exhibit a lower level


See: R. Petrov, R. Khaitov, "Genetics of Immunity and Vaccines of the Future", Science in the USSR, No. 5, 1981; R. Khaitov, "Immune System in Focus", Science in Russia, No. 1, 2004.--Ed.


R. Petrov (Member of the Russian Academy of Sciences), and R. Khaitov (Member of the Russian Academy of Medicine) merited a RF State Prize in Science and Technology (2011) for basic and applied works in immunology done over forty years.--Ed.

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This dendrogram shows similarities and differences in the immune response of ethnic groups in Russia and former Soviet republics. Bold, groups examined by the Immunology Institute.



of polymorphism (manifest in HLA homozygotic genotypes containing a double set of the same genes), which increases the probability of an inadequate protective response to particular pathogens. It was found back in the 1970s and 1980s that the HLA compatibility of a married couple is responsible for a higher rate of reproduction pathologies (like idiopathic, or essential sterility, regular gestation problems and miscarriages, grave toxicoses of pregnancy). Corrective measures of such gestative complications were developed in our country in the 1980s. Such preventive steps, however, result in a well-nigh 100 percent chance of HLA homozygotic progeny, and the higher risk of an inadequate immune response to a variety of infectious agents. In addition, HLA homozygotes are more predisposed to oncological and autoimmune diseases*, the result of faulty immune recognition. In malignancies the organism fails to recognize its degenerative cells. In autoimmune illnesses the organism does not spot intact cells on account of the presence in the patients' genotype of antigens common with those present in the pathogens of endured diseases. Consequently, parents saddled with reproductive problems (common HLA antigens in the genotype) gave to choose: either not conceive a child or resort to immunotherapy that may help in giving birth to a baby having no lower immune status problems.


Yet another line of immunogenetics research, "HLA and Diseases", came up in the 1970s. Concrete HLA antibodies were found to be associated with the predisposition or with the resistance to particular pathologies. Most manifest is the association with autoimmune diseases, including socially significant ones, such as type I diabetes mellitus (sugar diabetes), systemic erythematosus and ankylosing spondylosis, also known as rheumatoid spondylitis, or Marie's disease. Such associations were also identified between HLA and definite forms of infectious and oncological diseases.


Broad international studies in "HLA and Diseases" gave birth to another research trend, "HLA and Anthropology". Associations of concrete HLA antigens with


* Self-inflicted diseases of the organism causing damage to its organs and tissues through its immune system.--Ed.

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HLA system structure.


diseases varied significantly in their manifestation depending on the race and nationality of a test group.


Such evidence spurred comparative studies on HLA polymorphism in particular ethnic groups in different parts of the world. The first results of these studies were summed up at the 11th International Workshop and Conference on HLA in Yokohama, Japan, in 1991. Taking part were more than 3,000 scientists representing more than 2,000 research collectives. Immunology Institute researchers (Moscow) were awarded a medal for their signal contribution to the "HLA and Anthropology" program prioritized in the work of the above forums.


By now it has become possible to look into the tie-in among so many populations and ethnic groups across the world. HLA polymorphism is employed for such purposes because this genetic system is most varied and thus most informative. It opens up fresh opportunities for an international exchange of organ and tissue transplants (above all hematogenic stem cells, HSC).


The 11th International Workshop became the first scientific forum that came to deal with data obtained in many countries in research involving both proteomic and genomic analysis. Our Immunology Institute was taking an active part in this work. The genomic analysis of the HLA system became possible thanks to Kerry Mullis of the United States (Nobel Prize, 1993) who, in 1985, evolved a method of polymerase chain reaction (PCR), accessible for broad molecular-genetic studies.


The transition from proteomic to molecular-genetic methods of HLA research--effected also within the framework of the above international programs--was instrumental in an all-round breakthrough in human immunogenetics. Most of these achievements came to be interconnected. Thus, the number of identified HLA specificities has soared from 138 protein antigens to 7,000 allele variants of H LA genes.


These genes are ordered in three basic classes. Class I comprises genes A, B, C, E, F and G (the letters indicate the order of identification) ensuring the effector link of immunity and implicated in reproduction. Class 11 genes take in DR, DQ and DP, the genes whose products make for the immunological recognition of foreign agents (the basic function of immune response genes). In addition, mapped in the region of class II HLA genes are what we call "nonclassical" genes LMP, TAP, DM, CLIP and others responsible for the "recovery" of an immunodominant peptide from an antigen and its transportation

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Assigned to genes controlling the processing and presentation of immunodominant genes are HLA-TAP and LMP genes responsible for the function of class I HLA molecules, HLA-CLIP and - DM responsible for the function of class II HLA molecules.


to the respective peptide-binding sites of an HLA molecule. Localized in the region of Class III genes are C3 genes responsible for the complement function as well as TNF encoding the proteins of the tumor necrosis factor, and HSP coding for heat-shock proteins, etc. These genes carry out a similar function by providing a "nonspecific" protection of the organism against foreign agents (though skipping the stage of identification of genetically foreign agents).


It was quite natural for the molecular-genetic identification method to find its first hands-on application in clinical practice. Back in the 1980s the selection of his-to-compatible donor-recipient pairs could be relatively effective in organ and tissue transplantation. Today HLA identification on the basis of molecular genetic methods makes it possible to select a histocompatible bone marrow, or rather HSC cells for patients covered by international exchanges of this material. Unfortunately Russia is still not taking an active part in such exchanges not because of medicobiological but rather, because of legal and organizational aspects. Meanwhile international cooperation is a necessary condition for clinical trans-plantation or HSC stem cells, what with an extremely high level of diversity of HLA genes. For example, the probability of their concurrence for adequate HSC transplantation in two arbitrarily chosen unrelated individuals is one in a million on the average. As to related (kindred) donors, the brothers/sisters pairs are incompatible in most cases. Siblings (brothers-sisters) are only 25 percent compatible. In Russia as well as in most European countries and the United States, where large families with many children are not common, transplantations of kindred stem cells have little, or no, prospect.


Effective centralized exchanges of HSC stem cells have become possible only with the setting up of the World Association of Volunteer Donors, now over 17 mln strong, ready to donate stem cells to unknown patients all over the world.


We have already said that the HLA system is the most polymorphic among other genetic systems of man. This fact is thought to ensure the best survival chances of Homo sapiens as a species, for instance, in its long record of many centuries in combating infections. The immune

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Interpopulation differences in the genetically inherent occurrence of HIV immunity to HIV in Russia and neighboring countries.


system should identify any foreign agent or pathogen and give an adequate response to it. This is now a fact thanks to proteomic and molecular-genetic studies of the last two decades when it became clear that the immune function of H LA genes and their products is not at all restricted to the provision of an immunodominant peptide to T-cell receptors, and a subsequent immune response. Aided by the "nonclassical" HLA molecules, the HLA system controls all stages of the "recovery" of immunodominant peptides from foreign molecules and cells (from bacterial cells, too) and the delivery of these peptides to the antigen-bearing structures of HLA molecules that, upon the binding of peptides to corresponding sites, may be expressed on the surface of cells and join actively in the immune response. Malfunctions of "nonclassical" genes and their products are fraught with grave immunodeficiencies, including infectious, oncological and autoimmune diseases.


Needless to say, one single organism is unable to possess a high level of genetic diversity--high enough to ensure the presence of sites in the antigen-recognizing groove and thus identify an invading pathogen. Yet this problem can be tackled on a population level, where the combination of recognizing sites among individual representatives of various ethnic groups is remarkable for a great diversity. Realizing the "Human Genome" program, biomedicine has scored a spectacular achievement in elucidating the role of genetic polymorphism on a level of single nucleotide substitutions (Single Nucleotide Polymorphism, SNP). Certain mutations occurring thereby (biologically advantageous to the organism in the first place) are fixed in the human genome to become variants of an initial polymorphous gene.


The HLA system is a graphic example of SNP that comprises, as we have said above, over 7,000 allele variants of genes fixed in the genome by dint of certain biological expediency. As a mater of fact, a large part of SNP variants of one and the same gene carries out functions different from and even contrary to those of the basic (wild) gene. The polymorphism formative process on a SNP level within the HLA system is an ocular example of the positive biological role of mutations giving rise to new

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allele variants of the immune response genes fixed in the genome. This factor in particular ensures the survival of man in an aggressive environment, as supported by data on the formation of present-day HLA profiles* of populations in different parts of the world.


Thus, the haplotype HLA-A1-B8-DR3 is a classical immunogenetic marker for Caucasoids--it occurs in them far more frequently than among the other races. Studying this haplotype, Walter Bodmer of Great Britain suggested in the 1970s: this excess is due to the advantage of Caucasoids in surviving the pandemics of antiquity and the Middle Ages. Jean Dausset, the immunogenetics founder, has lent support to this hypothesis.


In the 1980s our research center carried out a series of works in this field to find that the presence of this haplotype and constituent antigens is associated with immunity indicators now assigned to the basic effectors of congenital immunity (natural killer cells, phagocytes, and the like). Congenital immunity performs a primary function in protecting organism against foreign aggressive agents and safeguarding it against pathogenic viruses, bacteria and carcinomas. The encounter of American Indians with European colonists had a tragic end for native Americans, for one, because the propagation level of the above HLA haplotype and, accordingly, the level of their congenital immunity was, and still is, very low to provide effective safeguards against the imported infectious agents.


It would be in place to note here that the Caucasoids still have to pay a dear price for the high presence of the HLA-A1-B8-DR3 haplotype associated with the autoimmune diseases, including sugar diabetes of type I and other endocrine pathologies.


Remarkably, the Mongoloids (Orientals), the world's most populous race, show a very low percentage of autoimmune pathologies in the morbidity structure. Uzbeks are perhaps the only exception--they are the world's leaders in the occurrence of type I diabetes. In this ethnic group of Mongoloids the occurrence rate of HLA-A1-B8-DR3 is close to those of the Caucasoids.


Even though the above examples are taken from human history, such mechanisms may have a part to play in our time and age, too. This is true of the scourge of the 20th and 21st centuries, AIDS (Acquired Immunodeficiency Syndrome). The point is that its virus hits immune system cells that carry the CD4+ receptor (characteristic of the subpopulation of immunocompetent cells, the T-helpers, directly implicated in the initiation and control of the immune response). This receptor is a "gate" for the HIV (human immunodeficiency virus) into the human immune system. This process, however, also involves another receptor, CCR5, controlled by the immune response genes unrelated to HLA. There is also CCR5delta32 among allele variants arising in consequence of CCR5 mutation. Unlike the basic gene it is not bound to HIV and in this fashion keeps it from invading cells and thus protects the organism. This process, however, takes place only if the receptor is a product of the homozygotic variant CCR5delta32. If it is present in the heterozygotic form, or on one chromosome, the disease may be on, though in a less aggressive form.


Our Immunology Institute has studied the occurrence of these variants in a group of about 1,000 "healthy" individuals of 10 ethnic groups of two races (Caucasoids and Mongoloids) populating the territory of Russia and former Soviet republics. The homozygotic pattern according to CCR5delta32 is most frequent in European Russia's northwest, but it declines towards southeast.


These data demonstrate: today aggressive factors of the environment may be implicated in forming interpopulation differences within the human immunogenome. This trend is in both for infectious pathogens and for such deleterious factors as radiation.


We would like to add in conclusion that the system of immune response genes protects its diversity and excludes (in the animal kingdom anyway) homozygotes according to the above-indicated immune response genes. These safeguards ensure the biological advantage of heterozygotes having, by the way, far lower risks than homozygotes in the incidence of nearly all socially significant diseases of man.


* HLA profiles, frequencies of HLA antigens (gens) occurrence in a population.--Auth.

Опубликовано на Порталусе 18 октября 2021 года

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